Abstract 363: Lysosomal Lipid Accumulation and Dysregulation of Downstream Cholesterol Homeostasis in Human Arterial Smooth Muscle Cells
Bibliographic record
Abstract
Background and Hypothesis: Previously we reported that ≥ 50% of the foam cells in human coronary artery atherosclerosis are smooth muscle cell (SMC) derived, and that the rate-limiting cholesterol exporter, ATP-binding cassette transporter protein A1 (ABCA1), has reduced expression in SMCs compared to leukocytes in the intima. Upregulation of ABCA1 expression is dependent on normal flux of lipoprotein-derived cholesterol out of lysosomes and the subsequent generation of 27-hydroxycholesterol (27-OHC). Excess lipoprotein-derived cholesterol is also converted to cholesteryl esters (CE) through the actions of acyl-coA cholesterol acyltransferase (ACAT). Processes by which macrophages store lipoprotein-derived cholesterol in cytosolic and lysosomal compartments are well described, whereas less is known about SMCs. Hypothesis: We hypothesize that preferential SMC foam cell formation and the observed derangement in ABCA1 expression are associated with increased lysosomal sequestration of atherogenic lipids. Methods and Results: Human aortic SMCs and human monocyte-derived macrophages (HMMs) were loaded with aggregated LDL (agLDL) for 24 hrs, followed by a 24 hr equilibration without lipids to allow processing of lipoproteins. Data are presented as mean±SEM. In response to agLDL, CE content (nmol/mg protein) measured by LC/MS/MS increased from 2.2±1.3 to 277.0±18.2 in HMMs, and 3.5±5.3 to 46.8±14.5 in SMCs (n=9). Confocal microscopy indicated elevated lysosomal lipid accumulation in SMCs compared to HMMs. Levels of 27-OHC (ng/mg protein) as measured by LC/MS/MS increased from 80.9±9.5 to 281.4±22.7 (3.5-fold) in HMMs, and 0.7±0.2 to 1.5±0.3 (1.4-fold) in SMCs (n=9). ACAT activity, measured by the incorporation of 14 C-labelled oleate (pmol/mg protein), increased from 21.0±1.7 to 678.1±110.9 (32.2-fold) in HMMs, and 55.6±3.3 to 133.7±15.2 (2.4-fold) in SMCs (n=16). By Western blot, fold change in ABCA1 with exposure to agLDL was 2.3±0.3 in HMMs and 1.3±0.2 in SMCs (n=7-10). Conclusions: Accumulation of atherogenic lipids in the lysosomes of SMCs provides a potential mechanism for the reduced ABCA1 expression and preferential formation of foam cells by arterial SMCs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".